title: Identification of methyl violet 2B as a novel blocker of focal adhesion kinase signaling pathway in cancer cells.
abstract: The focal adhesion kinase (FAK) signaling cascade in cancer cells was profoundly inhibited by methyl violet 2B identified with the structure-based virtual screening. Methyl violet 2B was shown to be a non-competitive inhibitor of full-length FAK enzyme vs. ATP. It turned out that methyl violet 2B possesses extremely high kinase selectivity in biochemical kinase profiling using a large panel of kinases. Anti-proliferative activity measurement against several different cancer cells and Western blot analysis showed that this substance is capable of suppressing significantly the proliferation of cancer cells and is able to strongly block FAK/AKT/MAPK signaling pathways in a dose dependent manner at low nanomolar concentration. Especially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1nM of methyl violet 2B in A375P cancer cells. To the best of our knowledge, it has never been reported that methyl violet possesses anti-cancer effects. Moreover, methyl violet 2B significantly inhibited FER kinase phosphorylation that activates FAK in cell. In addition, methyl violet 2B was found to induce cell apoptosis and to exhibit strong inhibitory effects on the focal adhesion, invasion, and migration of A375P cancer cells at low nanomolar concentrations. Taken together, these results show that methyl violet 2B is a novel, potent and selective blocker of FAK signaling cascade, which displays strong anti-proliferative activities against a variety of human cancer cells and suppresses adhesion/migration/invasion of tumor cells.
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, 39-1, Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
mesh_terms: D045744:Cell Line, Tumor; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005840:Gentian Violet / Q000494:pharmacology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005840:Gentian Violet
keywords: Adhesion/migration/invasion suppression; FAK signaling blocker; FER phosphorylation inhibition; Focal adhesion kinase; Methyl violet 2B; Structure-based virtual screening